ROLE OF HSP 110 IN TAUOPATHY

HSP 110 在 Tauopathy 中的作用

• 批准号: 8394589
• 负责人: NAHID F MIVECHI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394589
• 关键词: Acute Brain Injuries; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Appearance; Applications Grants; Axon; Behavioral; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Complex; Development; Disease; Down Syndrome; Event; Exhibits; Exposure to; Family member; Future; Generations; Goals; Heat shock proteins; Impaired cognition; In Vitro; Inherited; Injury; Isomerase; Knowledge; Life; Location; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Chaperones; Molecular Machines; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Pattern; Pick Disease of the Brain; Play; Production; Protein Dephosphorylation; Proteins; Records; Recovery; Risk; Role; Senile Plaques; Social Problems; Tauopathies; Testing; Tg2576; Therapeutic; Toxic effect; Traumatic Brain Injury; Variant; Veterans; Wild Type Mouse; age related; amyloid precursor protein processing; brain tissue; combat; corticobasal degeneration; disability; hyperphosphorylated tau; in vivo; mouse model; mutant; pre-clinical; prevent; protein degradation; protein misfolding; response; tau Proteins; tau aggregation

Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) following TBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathological hallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles (NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, plays a pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins (Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Their role in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. As such, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissue following TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discovery that hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) and neurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leads to tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to be involved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with mice expressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110- /-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting a role for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by which Hsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of this grant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau and are protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we will determine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i are substrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will use hsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo; since the expression of Hsps increases following environmental insults and because TBI is known to increase the risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recovery from TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will also examine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i in senile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury.

对退伍军人医疗保健的潜在影响是创伤性脑损伤(TBI)，这是主要的死亡原因 35岁以下的人和残疾，以及在战斗中经常发生的情况，导致严重的缺陷 在认知和社交问题和显著的淀粉样β蛋白(A？)生成中。此外，有证据表明， 淀粉样蛋白沉积增加和发生阿尔茨海默病(AD)的风险增加 TBI。然而，我们对阿尔茨海默病的治疗知识仍然不完整。神经病理学 阿尔茨海默病和其他神经官能症的特征包括老年斑和/或神经原纤维缠结 (NFTS)导致神经元退化。临床记录表明，定位于轴突的tau在 在与蛋白质功能障碍有关的神经退行性疾病中起着关键作用。热休克蛋白 热休克蛋白(HSP110)和热休克蛋白70i(HSP70i)在暴露于环境侮辱后高度表达。他们的 研究表明，几种热休克蛋白是NFTs的组成部分，这在神经元疾病中的作用得到了支持。AS 在含有tau的NFT中，在AD脑的神经炎性斑块中，以及在脑组织中，已经检测到这样的HSPs 跟随着TBI。我们的发现直接表明了热休克蛋白在神经退行性疾病中的作用。 Hsp110-/-小鼠表现出与年龄相关的过度磷酸化tau(p-tau)和 神经退行性变。我们还发现了Hsp110、tau和Pin1异构酶，它们的缺失在小鼠体内导致了 相互作用在相同的复合体中。自从Hsp110家族成员以来，Hsp70已经被证明是 参与细胞中淀粉样前体蛋白(APP)的处理，我们测试了hsp110-/-小鼠是否与小鼠杂交 表达突变的APP(Tg2576+)在体内表现出加速的病理变化。结果表明，hsp110确实是- /-Tg2576+小鼠比hsp110+/+Tg2576+小鼠更年轻地表现出神经性斑块，这强烈表明 HSP110(和HSP70i)在体内AD病理中的作用因此，理解通过什么机制 HSP110和HSP70i防止p-tau蓄积，减少AD病理，并影响脑损伤是本课题的主题 批准申请。我们推测HSP110和HSP70i对于tau和hsp70i的适当去磷酸化是至关重要的。 在AD期间和脑外伤后具有保护作用，并防止神经元死亡。在我们建议的研究中，我们会 确定HSP110、HSP70i、tau的表达和轴突内定位，或HSP110和HSP70i是否 Pin1的底物。作为与肌萎缩侧索硬化症相关的神经退行性疾病的例子，我们将使用 HSP110-/-Tg2576+小鼠建立Hsp110复合体在体内APP加工和A？产生中的作用； 由于HSPs的表达在环境侮辱之后增加，并且因为已知TBI增加 阿尔茨海默病的风险，我们将调查HSP110和HSP70i的存在是否在恢复中起作用 如果短暂增加热休克蛋白水平加速了脑损伤后的恢复，我们还将 检查健康或AD患者的脑组织切片以确定HSP110、HSP70i在 老年斑块；最后，我们将使用接受脑外伤患者的脑脊液(CSF)来 确定损伤后HSP110或HSP70i的水平是否与脑损伤的程度相关。